Acute Myeloid Leukemia In CR1 Research Articles

Expanded indications for allogeneic stem cell transplantation in patients with myeloid malignancies

Hematopoietic stem cell transplantation (SCT) can be curative for myeloid malignancies such as acute myeloid leukemia (AML). Advancements in human leukocyte antigen (HLA) typing and supportive care have improved the risk-benefit ratio for SCT, expanding its indications. Allogeneic SCT is an established treatment for AML with intermediate-risk and high-risk cytogenetics in first complete remission (CR1), from matched related donors (MRDs). Similar survival benefits are seen for AML in CR1 with unfavorable cytogenetics using matched unrelated donors (URDs). Molecular characterization has delineated patients with AML at higher risk with normal cytogenetics [e.g., FLT3-internal tandem duplication (ITD)+]. The outcomes of allogeneic SCT are comparable in patients with therapy-related or de-novo AML when adjusted for disease status and cytogenetics. In patients lacking a MRD, the majority will have a suitable alternative using an URD, umbilical cord blood, or haploidentical-related donors; outcomes are either comparable or relatively acceptable compared to a matched sibling donor. Comorbidity indices aid in identifying elderly and debilitated patients who may benefit from SCT; the application of SCT has been further increased by reduced-intensity conditioning regimens. Allogeneic SCT may be extended to almost all patients with AML, and integration of toxicity and relapse risks will determine the best approach for allogeneic SCT in the future.

Transplantation Outcomes of 8/8-Matched Unrelated Donors Compared with Matched Siblings and Autologous Transplantation for Acute Myeloid Leukemia with Intermediate Cytogenetics in First Remission

There have been a few multicenter or registry data assessing the feasibility of unrelated donors (URD) in acute myeloid leukemia (AML) compared to HLA-matched sibling donors (MSD). These studies suggest that MSD and HLA-matched URD have comparable outcomes. However, the small number of patients in first complete remission (CR1) and the lack of high-resolution HLA typing in these studies make it difficult to clearly determine the role of 8/8-matched URD in patients with AML CR1. Furthermore, using 8/8-matched URD is not currently standard practice in patients with AML CR1 having intermediate cytogenetics, particularly those without poor risk features, when MSD are not available. These patients are also candidates for non-allogeneic stem cell transplantation (allo-SCT) therapy, such as autologous peripheral blood stem cell transplantation (auto-PBSCT). In order to clarify the role of 8/8-mateched URD in these patients, transplantation outcomes should be compared with non-allo-SCT therapy as well as MSD. Between 2002 and 2009, 567 adult patients with AML underwent transplantation from MSD, URD, and autologous sources. According to the risk-adapted treatment strategy, AML CR1 with intermediate cytogenetics received allo-SCT as a post-remission treatment, if MSD or 8/8-matched URD was available. Patients with no available donor received autologous transplantation. To determine the role of 8/8-matched URD on transplantation outcomes in patients with intermediate cytogenetics, we evaluated 288 patients with intermediate cytogenetics who underwent transplantation from autologous sources (n=89) or allogeneic donors (n=199) consisting of 8/8-matched URD (n=54) and MSD (n=145) at CR1. In multivariate analyses, 8/8-matched URD had comparable 6-year overall survival (OS, P=0.997), disease-free survival (DFS, P=0.951), and relapse (P=0.672) to MSD, whereas 8/8-matched URD had a higher OS (P=0.070) and DFS (P=0.035) with lower relapse (P=0.009) than autologous transplantation. No difference in non-relapse mortality was observed according to donor type. Notably, these equivalent or superior outcomes of 8/8-matched URD compared with MSD or autologous transplantation, respectively, were particularly evident in patients without poor risk features (n=200), such as older age, hyperleukocytosis at diagnosis, and myelodysplasia-related changes, who are not usual candidates for URD transplantation. In conclusion, this study confirmed the comparable outcomes of 8/8-matched URD with MSD in AML CR1 with intermediate cytogenetics. Additionally, this study strongly suggests that 8/8-matched URD is preferable to auto-PBSCT in AML CR1 with intermediate cytogenetics, when MSD are not available. Finally, our data indicate that 8/8-matched URD are feasible next option in AML CR1 with intermediate cytogenetics, when lacking MSD, even in patients without poor risk features.

A Phase II Study of Allogeneic Transplantation for Older Patients with AML in First Complete Remission Using a Reduced Intensity Conditioning Regimen: Results From CALGB 100103/BMT CTN 0502

AbstractAbstract 230▪▪This icon denotes a clinically relevant abstractThe prognosis for patients (pts) with acute myeloid leukemia (AML) who are aged 60 years or older at the time of initial diagnosis is poor. Even for pts achieving a first complete remission (CR1), prospects for long-term survival are poor due to the very high risk of relapse. Conventional myeloablative conditioning followed by allogeneic blood or marrow transplantation is associated with significantly less relapse compared with conventional chemotherapy when performed in younger pts with AML in CR1. However, the toxicity of this approach in older pts is prohibitive. A reduced intensity conditioning (RIC) regimen may mitigate the risk of early toxicity and while early results in older AML pts have been encouraging and suggest disease free survival (DFS) rates above 30% at 3 yrs (Farag et al, Biol Blood Marrow Transplant 2011), most data are retrospective and pts have not been treated uniformly. We therefore sought to determine the effectiveness of a uniform RIC regimen given to older pts with AML in CR1 on a prospective multi-center phase II trial conducted by the Alliance (formerly Cancer and Leukemia Group B (CALGB)) and the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). The study, activated in 2004, was initially limited to recipients of a matched related donor (MRD) graft but was amended in 2006 to include matched unrelated donor grafts (URD). The primary endpoint of the study was 2-year DFS. We hypothesized that DFS at 2-years would exceed 20% and powered the study to detect a 2-year DFS probability of 35% for URD recipients. We focused the primary analysis on URD recipients since the majority of older pts require an URD graft. Eligible pts were from 60–74 years old inclusive, had AML in CR1 following induction chemotherapy, availability of a 6/6 MRD or 8/8 URD, and absence of significant end-organ damage prior to transplantation. Adverse events (AE) were initially recorded according to NCI-CTCAE v3.0, amended to v4.0 in 10/2010. Accrual was completed in 12/2011. 132 pts were registered at 21 centers and 123 transplanted (MRD (47%); URD (53%). All donor grafts were mobilized and collected following G-CSF (PBSC). The median age of pts was 65 (range 60–74) and 76 pts (62%) were male. At diagnosis, 67% had an intermediate risk karyotype, 20% adverse risk, <1% favorable, and in 11% data were missing. More than 90% achieved CR following standard “7+3” based induction. CR1 was achieved after 1 (59%) or 2 (41%) induction cycles. Consolidation therapy was administered for one (50%) or two (24%) cycles and 17% received no consolidation with data missing in 9%. All but the initial 8 MRD recipients (who received fludarabine and busulfan alone) were conditioned with the same regimen containing fludarabine (30mg/m2/day × 5), busulfan (6.4mg/kg IV total dose), and antithymocyte globulin (ATG; thymoglobulin) (7.5mg/kg total dose). Only one case of primary graft failure was reported. With a median follow-up of 3.3 yrs, the results in the 123 transplanted pts are depicted below:EventCumulative incidence at 100 days* or 2yrs†95% CIAcute GVHD 2-49.4%*4.1–15%Acute GVHD 3-43.4%*1.2–6.7%Chronic GVHD26%†17–34%Relapse47%†37–57%Treatment related mortality (TRM)14%†7.2–21%EventProbability at 2 yrs95% CIDFS39%30–50%DFS URD only38%26–55%Overall survival (all pts)46%36–57%The rates of both acute and chronic GVHD as well as TRM were relatively low. There were 81 grade 3–5 non-hematologic AE recorded, including 7 grade 5 (4 infections, 1 each cardiac, pulmonary, and second malignancy). Relapse was the most common cause of death. In conclusion, the results of this first prospective US cooperative group trial conducted in a homogeneously treated group of older AML patients in CR1 demonstrate the feasibility and effectiveness of RIC allografting using MRD or URD PBSC grafts. DFS appears better following a RIC allograft compared to results achieved historically after conventional therapies, warranting prospective comparison in pts with contemporary cytogenetic and molecular disease characterization. Future research should also focus on preventing disease relapse after RIC allografting in this population. Disclosures:Devine:Sanofi: Honoraria, Research Funding. Off Label Use: Antithymocyte globulin for GVHD prophylaxis is included in the abstract. Vij:Millennium: Speakers Bureau. Shea:Otsuka: Research Funding.

Transplantation From 8/8-Matched or 7/8-Matched Unrelated Donors Compared with HLA-Matched Siblings in Acute Myeloid Leukemia in First Complete Remission

AbstractAbstract 2040▪▪This icon denotes a clinically relevant abstractComparable survival after 8/8-matched unrelated donor (URD) transplantation with HLA-matched siblings (MSD) has been reported in AML from a few multicenter studies. However, the role of 8/8-matched URD in acute myeloid leukemia (AML) with first complete remission (CR1) is uncertain because they applied various methods for HLA typing, such as low or intermediate resolution or partly high resolution (HR) typing, and/or included various disease status at transplantation. Additionally, there have been few studies comparing the clinical outcomes of 7/8-matched URD with current standard donors, such as MSD or 8/8-matched URD, particularly in AML, as a single disease.According to the risk-adapted treatment strategy, AML CR1 with intermediate or adverse cytogenetics received allogenetic transplantation as a post-remission treatment, if MSD or 8/8-matched URD was available. Patients with no available donor received 7/8-matched URD or autologous transplantation (only intermediate cytogenetics). Among 567 consecutive adult patients with AML who underwent transplantation between January 2002 and December 2009, in order to investigate the role of URD type in AML CR1, we assessed the transplantation outcomes of 8/8-matched URD (n=59) or 7/8-matched URD (n=36) classified by HR HLA typing, compared to MSD (n=165). Only intermediate or adverse cytogenetics was included, and we defined high-risk group as having one of the poor risk features, including adverse cytogenetics, hyperleukocytosis at diagnosis (over 100×109/L), older age over 60 years, or AML with myelodysplasia-related changes.In all, multivariate analyses showed that 8/8-matched URD had comparable 5-year disease-free survival (DFS; HR, 0.94; P=0.803), relapse (HR, 1.03; P=0.935), and non-relapse mortality (NRM; HR, 0.62; P=0.294) to MSD, while 7/8-matched URD had higher relapse (HR, 1.95; P=0.034) and a lower trend for DFS (HR, 1.47; P=0.154) than MSD without the difference in NRM (HR, 0.61; P=0.390). The equivalent outcomes of 8/8-matched URD were consistent irrespective of risk groups (high or standard). Particularly, only in standard-risk group, 7/8-matched URD (n=18) failed to show any benefit compared to concurrently performed autologous transplantation (n=67), contrasting to the superior survival of 8/8-matched URD (n=32) as well as MSD (n=108).In conclusion, the equivalent outcomes between MSD and 8/8-matched URD, irrespective of risk-group in AML CR1, suggest that 8/8-matched URD is useful for standard-risk as well as high-risk group of AML CR1, when lacking of MSD. On the other hand, the inferior outcome of 7/8-matched URD raise the necessity of trials comparing with other alternative graft sources, such as umbilical cord bloods or haploidentical family donors, particularly in AML with high-risk group. Disclosures:No relevant conflicts of interest to declare.

Equivalent Outcome Between Older Siblings and Unrelated Donors After Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation for Patients Older Than 50 Years with Acute Myeloid Leukemia in First Complete Remission: A Report From the ALWP of EBMT

AbstractAbstract ▪961▪This icon denotes a clinically relevant abstract Background:Current data indicates that allogeneic hematopoietic stem cell transplantation (HSCT) provides identical long-term survival for patients (pts) with acute myeloid leukemia (AML) receiving grafts from matched 8/8 unrelated donor (MUD) or matched sibling donor (MSD) after reduced intensity conditioning (RIC) regimen. Given those results, one may question the requirement for an “older” MSD when a healthy younger MUD is available. This study assessed the impact of older age of MSD on outcomes post-HSCT for pts older than 50 years with AML in first complete remission (CR1) transplanted after a RIC regimen. Patients and methods:From January 2000 to December 2010, this retrospective multi-center study included 1102 pts with AML in CR1 who received PBSC after a RIC regimen, either from MSD (n=854) or from 8/8 HLA MUD (n=248). Conditioning regimen was fludarabine-based in 95% of the pts and Graft versus Host Disease (GvHD) prophylaxis consisted of cyclosporine plus MMF in 42% of cases. To address the role of donor age in our population, 3 groups of pts were defined: pts who were transplanted from a MUD (“MUD group”), pts who received their graft from a sibling aged less than 60 years old (“MSD<60 group”) and pts who were transplanted from a sibling aged of 60 years old or more (“MSD360 group”). Results:Patient characteristics were similar between the 3 groups for gender, disease distribution (FAB classification) and cytogenetic risks (MRC classification). Recipients were younger in the MSD<60 group (57 years versus 60 and 61 years for MUD and MSD360, respectively, p<0.001). Donors were younger for MUD (median age 35 years versus 53 years and 64 years for MSD<60 and MSD360 respectively, p<0.001). In the MUD group, pts were transplanted more recently (2009 versus 2006 and 2007 for MSD<60 and MSD360 respectively, p<0.001), with a longer time interval between diagnosis and HSCT (184 days versus 154 days and 151 days for MSD<60 and MSD360 respectively, p<0.001) and the conditioning regimen included more ATG (p< 0.0001). The median follow-up was 24 months (range, 2–122) for MUD, 42 months (range, 1.5–140) for MSD<60 and 33 months (range, 1–129) for MSD360. During evolution, the cumulative incidence (CI) of acute GvHD was 28% in MUD versus 20% and 17% in MSD<60 and MSD360, respectively (p=0.006) while the CI of chronic GvHD at 2 years was about 50% in each group (p=0.93). CI of treatment related mortality (TRM) and relapse as well as leukemia free survival (LFS) and overall survival (OS) were not different at 2 years between the 3 groups (Table 1). In multivariate analysis, TRM was decreased in pts who received ATG in the conditioning regimen (HR: 0.62; 95%CI 0.41–0.95; p=0.03). A longer interval between AML diagnosis and CR1 (>median) was the only factor associated with relapse (Hazard ratio - HR: 1.35; 95%CI 1.05–1.74; p=0.02). Two independent factors were associated with worse LFS: a longer delay between AML diagnosis and CR1 (HR: 1.34; 95%CI 1.09–1.64; p=0.01) and CMV donor seropositivity (HR: 1.28; 95%CI 1.02–1.6; p=0.04). For pts alive after 2 years post HSCT (n=454), a significant higher rate of TRM was found in pts transplanted from MUD compared with the 2 other groups (Landmark analysis, Table 2). Conclusion:These data suggest equivalence of outcome using MUD, MSD<60 or MSD360 in pts older than 50 years with AML in CR1 transplanted after a RIC regimen. Until prospective studies are completed, this study supports the recommendation to consider HLA-identical donors for HSCT even after 60 years of age (if eligible for donation) prior to younger 8/8 MUD for pts with AML older than 50 years in CR1 after a RIC regimen.Table 1:2-years Cumulative Incidences of TRM, relapse, LFS and OSTRMRelapseLFSOSMUD15±229±355±356±3Sib and donor age <60 years14±130±252±263±2Sib and donor age 36015±233±352±357±3Pvalue0.460.560.740.06Table 2:Landmark analysis after 2 yearsMUD (n=84)TRMRelapseLFSOS21±85±372±974±9Sib and donor age <60 (n=252)5±211±283±390±2Sib and donor age 360 (n=96)7±316±477580±5Pvalue0.0090.370.740.06 Disclosures:No relevant conflicts of interest to declare.

Haploidentical Mismatched Allogeneic Versus Autologous Hematopoietic STEM CELL Transplantation in Adult Patients with ACUTE Myeloid Leukemia (AML) in First Complete Remission (CR1): A Pair-Matched Analysis From the Acute Leukemia Working Party of EBMT.

AbstractAbstract 3093▪▪This icon denotes a clinically relevant abstractIn the absence of a matched family donor, adult patients with AML in CR1 are nowadays usually offered, as a first choice, an allogeneic transplant from an alternative donor (haplomismatched donor or cord blood cells), but there has been thus far no demonstration that outcome when using an alternative donor would be superior to outcome following an autologous stem cell transplantation (ASCT).Between January 2000 and December 2010, 113 AML patients transplanted in CR1 with an haplo-mismatched family donor and 4444 patients autografted were reported to the EBMT registry. For the purpose of this analysis, we performed a matched pair analysis (113 haplo/226 autos) using age and interval from diagnosis to transplant as matching factors. The median follow up was 18 months (range, 1–128). Patients allografted were transplanted more recently (median year of transplant: 2008 vs 2004, p<10e-4), and they received more frequently total body irradiation in the pretransplant regimen (58% vs 17%). Engraftment following an haplo- mismatched transplant occurred in 93% of cases vs 99% after ASCT and recovery of ANC>500/mm3 was slightly delayed (15 days vs 13 days, p<10e-4). The outcome at two years, following an haplo mismatched transplant versus an ASCT was: LFS 44±5% vs 54±4% (p=0.008); OS 44±6 % vs 68±4% (p<10e-4); Non Relapse Mortality (NRM) 37±5% vs 2±2 ( p<10e-4) and Relapse Incidence (RI) 19±4% vs 43±4% (p<10e-4). Following an haplo mismatched transplantation the incidence of chronic extensive GVHD was 24+/− 6%. By multivariate analysis adjusted on year of transplantation, source of stem cells and TBI, the RI was no longer statistically different between the 2 groups, NRM was higher following haplo (HR=11.8; p<0.0001) and LFS was better following ASCT (HR=0.52; p=0.004).Though this study did not account for cytogenetics and molecular markers (data collection is ongoing), these results suggest that outcome following ASCT in CR1 may be better compared to outcome following a haplo-mismatched transplantation. Recent developments in both transplant approaches may change the results in the near future and may justify a randomized prospective study. Disclosures:No relevant conflicts of interest to declare.

Value of Pretransplantation Minimal Residual Disease in Acute Myeloid Leukemia and Myeloablative Hematopoietic Cell Transplantation.

AbstractAbstract 2510Relapse remains the main cause of treatment failure in patients with acute myeloid leukemia (AML) in first remission (CR1) after allogeneic hematopoietic stem cell transplantation (SCT). The detection of minimal residual disease (MRD) in AML has improved in the past years with multiparametric flow cytometry (MFC) and molecular analysis (RT-PCR). However the prognostic impact of pre-transplantation MRD and the outcome after SCT has not been well studied. The aim of this study was to evaluate pre-transplantation MRD in patients in first remission undergoing myeloablative allogeneic SCT.We retrospectively studied 35 consecutive patients receiving myeloablative SCT for AML in first cytologic remission after intensive chemotherapy with available MRD determination before transplant. MRD was studied by 4-color MFC on bone marrow aspirates, and quantitative RT-PCR (NPM1, WT1, MLL) on bone marrow and/or peripheral blood samples obtained within thirty days before transplant.Thirty-five patients consecutively transplanted in our institution between 1999 and 2012, and for which pre-transplant MRD data was available were analyzed (Table 1). Eighteen showed negative MRD pre-transplant whereas 17 showed positive values. Characteristics of patients were homogeneous between both groups, including number of chemotherapy cycles received before transplantation (Table 1).Within the MRD-negative group, 17 patients showed negative MRD by MFC (12 of them showed negative values also by PCR) and 1 patient showed negative MRD by PCR (MFC not available). Within the MRD-positive group, 9/17 (52%) patients showed MRD-positive values by MFC: in 5 cases MRD was also detected by PCR, only 1 showed negative PCR and in the remaining 3 cases, PCR was not available. On the other hand, in 8/17 (47%) patients MRD was not detected by MFC, however, PCR detected MRD in all of the cases in bone marrow (2), peripheral blood (4) or both samples (2).With a median follow-up of the whole series of 23 months, 2-years estimates of overall survival were 82% (95% CI, 97–55) and 30% (95% CI, 3–71) for MRD-negative and MRD-positive patients (p=0.045), respectively. Cumulative incidence of relapse were 21% (95% CI, 5–48) and 56% (95% CI 10–73) for MRD-negative and MRD-positive patients (p=0.11).In the MRD-negative group, cause of death was toxicity in 11% of the cases and relapse in 11%, while in the MRD-positive group, 17% of patients died due to toxicity and 23% due to relapse.Conclusions: Our data shows that the presence of MRD before allogeneic SCT in patients with AML in CR1 is associated with a significant worse OS rate compared to patients with negative MRD, as well as a tendency towards a higher risk of relapse. The detection of MRD by MFC correlates with the detection by PCR in most of the cases. However, in a significant group of patients, MRD was detected only by PCR. This could be related to differences in sensitivity between both methods. Further studies including larger series are needed to confirm these observations.Table 1Patient and Disease Characteristics by MRD statusPre-transplant MRDMRD-negativeMRD-positiveN=351817Age at transplant (median, R)36 (19-62)42 (19-68)Gender (male/female)8/1012/5Cytogenetics and molecular markersNormal/Intermediate risk77%83%FLT3+28%27%NPM1+/FLT3-6%7%FLT3-/NPM1-28%40%High-risk22%17%Secondary AML16%6%Cycles pre-transplantation (median, R)3 (2-5)3 (2-5)MRD detectionMFC only27%18%RT-PCR only5%0%Both68%82%Donor*HLA-identical sibling50%35%HLA-matched unrelated22%29%SCU-dual22%24%HLA-haploidentical related6%12%acute GVHD II-IV (n°/patients at risk)44% (8/18)24% (4/17)chronic GVHD lim/ext (n°/patients at risk)53% (8/15)57% (8/14)MRD: minimal residual disease, MFC: multiparametric flow cytometry, RT-PCR: real time PCR, GVHD: graft vs host disease, SCU-dual: single cord blood with co-infusion of selected CD34+ cells from a third party HLA-mismatched donor.*The MRD negative group includes 2 MAC SCU-dual cases with primary graft failure rescued immediatly by a second graft (1 Dual and 1 Haplo) using a RIC regimen. The MRD positive group includes 1 MAC SCU-dual case rescued immediatly by a second graft (1 Haplo). Disclosures:No relevant conflicts of interest to declare.

A Simple and Predictive Index for the Evaluation of Risk Stratification Following Hematopoietic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia in Remission.

Abstract 3066▪▪This icon denotes a clinically relevant abstract Background.The impact of risk-related parameters has not been defined in transplant settings. Design and methods.We analyzed the data of 255 consecutive patients (median age: 26) with acute myeloid leukemia (AML) in their first or second remission (CR1 or CR2) after haploidentical hematopoietic stem cell transplantation (HSCT). Results.Three parameters were found to be predictive of outcome: response after induction therapy, WBC count at diagnosis, and cytogenetics. These three factors were combined to yield two risk groups. The 2-year cumulative incidences of relapse for patients at low and high risk were 8% and 36% (p = 0.001), respectively. The three-year probabilities of leukemia-free survival (LFS) for these two groups were 80% and 52% (p = 0.001), respectively. Multivariate analysis for relapse and for LFS showed that not achieving CR after 2 courses of therapy was the strongest independent prognostic factor (p=0.001, and p=0.019, respectively). In addition, in a subgroup of patients with quantification of minimal residual disease (MRD) at the time of HSCT, positive MRD at this time point was correlated with a poor outcome. Conclusions.Our results suggest that the index is simple and predictive, so it might be applied to assist with risk-directed post-transplant therapy for young patients with AML in CR who have received myeloablative haploidentical HSCT. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Impact of Pretransplantation Risk Factors on Post Transplantation Outcome of Patients with Acute Myeloid Leukemia in Remission after Haploidentical Hematopoietic Stem Cell Transplantation

The impact of risk-related parameters has not been defined in transplantation settings. We wondered whether the currently recognized predictors could be used to categorize acute myeloid leukemia (AML) patients who underwent transplantation during remission into risk groups. We analyzed the data of 255 consecutive patients (median age, 26) with AML in their first or second remission (CR1 or CR2) after haploidentical hematopoietic stem cell transplantation (HSCT). Three parameters were found to be predictive of outcome: response after induction therapy, white blood cell count at diagnosis, and cytogenetics. These three factors were combined to yield two risk groups. The 2-year cumulative incidences of relapse for patients at low and high risk were 8% and 36% (P = .001), respectively. The 3-year probabilities of leukemia-free survival for these two groups were 80% and 52% (P = .001), respectively. Multivariate analysis for relapse and for leukemia-free survival showed that not achieving CR after two courses of therapy was the strongest independent prognostic factor (P = .001 and P = .028, respectively). In addition, in a subgroup of patients with quantification of minimal residual disease at the time of HSCT, positive minimal residual disease at this time point was correlated with a poor outcome. Our results suggest that the pretransplantation risk factors influence posttransplantation outcomes of patients with AML in CR after haploidentical HSCT and might be applicable to assist with risk-directed posttransplantation therapy.

Comparison of Autologous Hematopoietic Cell Transplantation and Chemotherapy as Postremission Treatment in Non-M3 Acute Myeloid Leukemia in First Complete Remission

Randomized trials of acute myeloid leukemia (AML) in first complete remission (CR1) showed that autologous hematopoietic cell transplantation (auto-HCT) improves relapse-free survival (RFS) but not overall survival (OS), compared with chemotherapy. Using a database of 2518 adult patients with AML in CR1, we conducted a 5-month landmark analysis and found that auto-HCT improves 3-year RFS but not OS compared with chemotherapy. A number of randomized trials in patients with AML in CR1 have been conducted and they showed that auto-HCT improves RFS but not OS, compared with chemotherapy. However, because these trials have had compliance problems, the value of auto-HCT still has not been clearly established. Using a database of 2518 adult patients with AML in CR1, we retrospectively analyzed the outcome of auto-HCT and compared it with intensive nonmyeloablative chemotherapy using landmark analyses. In 103 auto-HCT recipients, OS and RFS at 3 years from treatment were 65% and 57%, respectively. Multivariate analysis showed that unfavorable risk cytogenetics and entry into CR1 after 2 courses of induction treatment predicted a poor outcome. Because the median time interval between CR1 and auto-HCT was 153 days, landmark analyses at 5 months after CR1 were performed to compare 1290 patients who received chemotherapy alone (median age, 52 years; range, 16-70) with 103 who received auto-HCT (median age, 48 years; range, 16-67). Auto-HCT improves 3-year RFS (58% vs. 37%; P < .001) but not OS compared with chemotherapy alone. Among patients with unfavorable risk cytogenetics or those who required 2 courses to reach CR1, there was no significant difference in RFS between the 2 groups. Auto-HCT can be considered as a postremission therapy for AML patients with favorable or intermediate risk cytogenetics who achieve CR1 after a single course of induction treatment.

Allogeneic Stem Cell Transplantation for FLT3/ITD Positive Acute Myeloid Leukemia in CR1: Implication for Personalized Therapy to Prevent Early Relapses

Allogeneic Stem Cell Transplantation for FLT3/ITD Positive Acute Myeloid Leukemia in CR1: Implication for Personalized Therapy to Prevent Early Relapses

Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT) Improves Outcome As Compared to Conventional Consolidation in Patients Aged 40–60 Years with AML in CR1 with Apparent Greater Benefit for Reduced Intensity Rather Than Myeloablative Conditioning

Abstract 159AlloHSCT is considered standard consolidation therapy in adults with intermediate and poor-risk acute myeloid leukemia (AML) in first complete remission (CR1). Myeloablative (MAB) alloHSCT confers a survival advantage in younger AML patients (pts), but non-relapse mortality (NRM) may counterbalance a favorable effect on relapse, resulting in limited benefit in older pts. Meta-analyses have suggested that the advantage may already be limited beyond the age of 40. Reduced intensity conditioning (RIC) regimens were introduced to reduce NRM, while sparing graft versus leukemia (GVL) effects in older pts. Retrospective comparative studies have confirmed less NRM, but suggested that the net result in terms of overall outcome may not differ, as less NRM may be counterbalanced by more relapse. We evaluated within 4 consecutive prospective HOVON/SAKK cooperative studies (H29, H42, H42A, and H92) alloHSCT versus conventional consolidation in AML-CR1 pts between 40–60 years, with integrated comparison of alloHSCT using MAB versus RIC. Outcome measures included overall survival (OS), relapse free survival (RFS), as determined by relapse and NRM. The choice of conditioning regimen prior to alloHSCT (MAB or RIC) was solely based on center preference throughout the study period.1105 pts between 40 and 60 years of age with newly diagnosed AML receiving consolidation in CR1, were studied, including 237 pts proceeding to MAB and 144 to RIC alloHSCT. 724 pts were consolidated with either a third cycle of chemotherapy (n=470) or an autograft (n=254). More pts with unfavourable karyotype or late CR proceeded to alloHSCT than to alternative consolidation. Recipients of MAB or RIC were comparable with respect to age, leukemia risk-status, donor/recipient gender combination, CMV-serology, time from diagnosis to HSCT, EBMT risk-score, and follow-up (median 24 versus 25 months, in RIC and MAB, respectively). Significant differences with respect to stem cell source, graft manipulation, and year of transplant were observed, with a higher proportion of RIC in recent years.Pts with alloHSCT showed better OS (55% ± 4) than pts receiving alternative consolidation (46% ±2), p<0.01. In accordance with previous observations, pts in CR1, who received MAB alloHSCT had an OS of 50% (±3) at 5 years post HSCT, which appeared not different from consolidation by autografting, with OS of 49% (±3). However, pts receiving RIC alloHSCT experienced improved outcome with a 5 yr OS of 62% (±4%), p< 0.001, which improvement was noted among intermediate and poor-risk pts. RFS estimated 55% (±5%) versus 47% (±3%), in RIC and MAB pts, and RFS estimated 41% ±3% following autografting, p<0.001. The 5 yr cumulative incidence of relapse was not significantly different between RIC and MAB conditioned pts (36% ±4% versus 29% ±3%, p=0.56), but recipients of RIC alloHSCT experienced significant less NRM (9% ±3% versus 24% ±3%, p<0.001). Cox-regression analysis was performed with alloHSCT as a timedependent covariate and adjustment was done for age, time to CR, and cytogenetic risk. Comparing alloHSCT versus other consolidation treatments with respect to RFS, the overall hazard ratio (HR) for alloHSCT was 0.59 (95% CI, 0.49–0.70), P <.0001, while specific HR’s for RIC and MAB alloHSCT were 0.49 and 0.66, respectively, (both with p < 0.001). With endpoint OS, the overall HR for alloHSCT was 0.71 (95% CI, 0.76–0.90), p<0.0001, while the HR for RIC was 0.53 (0.40–0.71), p < 0.001, and for MAB alloHSCT 0.82 (0.66–1.01), p=0.07. In addition, cytogenetic risk appeared an important risk factor, determining RFS and OS (HR 2.08 95%CI, 1.84–2.34, p<0.0001).In conclusion, consolidation by alloHSCT significantly improves outcome as compared to either chemotherapy or autologous transplantation in CR1 pts aged 40–60 years, which was largely accounted for by RIC alloHSCT. These results suggest that: 1. similar to younger pts, alloHSCT can be considered standard consolidation therapy in intermediate and poor-risk AML in CR1, aged 40–60 years; 2. RIC and MAB alloHSCT may only slightly differ with respect to reduction of relapse in pts having benefited from intensive preceding induction/consolidation chemotherapy, while RIC is additionally associated with a significant reduction of NRM; 3. a prospective randomized trial comparing RIC and MAB in similarly pretreated AML pts, including younger pts in CR1, is advocated. Disclosures:Wijermans:Centocor Ortho Biotech Research & Development: Research Funding. Janssen:Novartis: Consultancy.

An Intergroup Randomised Trial of Standard Intensity Versus Reduced Intensity TBI-Based Conditioning In Patients with Acute Myeloid Leukemia in First Complete Remission

Abstract 157Allogeneic hematopoietic cell transplantation (HCT) remains the treatment approach with the lowest risk of relapse in patients with intermediate or high-risk acute myeloid leukemia (AML). The lower incidence of relapse achieved with allogeneic HCT is sometimes offset by the higher rate of transplant-related deaths mainly occurring during the first 12–24 months after the procedure. With the advent of reduced-intensity conditioning regimens, older and less fit patients have become eligible for allogeneic HCT. But still, there is some debate as to the optimum level of conditioning intensity in order to reduce non-relapse mortality without jeopardizing overall cytoreductive efficacy. Stimulated by the promising results of a phase II trial exploring the efficacy and toxicity of a regimen combining Fludarabine 30 mg/m2 for four days combined with 800 cGy fractionated total-body irradiation (TBI), we designed this study to compare the mentioned regimen with standard-intensity conditioning.Adult patients with AML in first complete remission (CR1) with standard or high-risk cytogenetics were randomly assigned with a ratio 1:1 to standard intensity conditioning (6 × 200 cGy TBI (1200cGy) over 3 days and Cyclophosphamide 60 mg/kg per day over 2 days (Arm A)) or TBI 4 × 200 cGy (800 cGy) combined with Fludarabine 30 mg/m2 daily over 4 days (Arm B). Antithymocyte globuline was infused at a cumulative dose of 60 mg/kg (3 × 20 mg/kg from day -3 to -1) in recipients of grafts from unrelated donors (UD). Pharmacologic prophylaxis of graft-versus-host disease (GvHD) was performed with CsA starting day -1 and Mtx on days 1, 3, 6 and 11. The primary endpoint was transplant-related mortality (TRM) within the first 12 months after transplantation Secondary end-points included overall as well as disease-free survival and acute and chronic GvHD.Between November 2004 and December 2009, 198 patients were registered in the trial. Three patients had to be excluded for the violation of inclusion criteria. The intent-to-treat (ITT) population, thus, consisted of 195 subjects (96 Arm A, 99 Arm B). Eleven patients did not receive the study treatment. Therefore, the per protocol analyses involved 184 patients (90 Arm A, 94 Arm B). Median age was 45 years (range 18–60). 46% were female. Intermediate risk and high risk karyotypes were present in 62% and 38% of the patients, respectively. 60% of the patients received grafts from matched sibling donors. Grafts from UD with at least 9 out of 10 HLA alleles (HLA-A, B, C, DRB1, DQB1) were infused in 40%. The majority of patients (89%) received G-CSF mobilised peripheral blood stem cells. Donor type, cytogenetic risk, type of induction regimen and age (18–40 vs. > 40) had been strata for randomisation and were therefore well balanced between both groups. Most patients had received double induction therapy using 3+7 combinations of anthracyclines and cytarabine.The evaluation of the primary endpoint in the per protocol population showed a lower incidence of TRM after 12 months in Arm B (8%, 95% Confidence interval (CI) 3–14% versus 17%, CI 9–24% in Arm A, p=0.048; ITT p=0.06). The difference in TRM at 12 months was even more pronounced in the subgroup of patients > 40 years (5% Arm B versus 20% Arm A, p=0.01). With a median follow-up of 27 (range 4–81) months for patients alive, the probability of overall survival three years after randomisation was 62 % in the reduced-intensity Arm B versus 59% in Arm A (p=0.28). Probabilities of disease-free survival were 60% and 56% for Arm B and Arm A (p=0.44), respectively. The cumulative incidence of grade II-IV acute GvHD until day 100 was 16% in Arm B versus 23% in Arm A (p=0.15). Cumulative incidences of relapse three years after transplantation were not different between both treatment arms albeit a different kinetic of relapse could be documented.This trial shows for the first time in a prospectively randomized design in patients with AML in CR1 that reduced-intensity conditioning can result in significantly lower early TRM without increasing relapse risk. Fludarabine combined with 800cGy fractionated TBI can be regarded as a valid alternative to standard intensity conditioning even in younger patients with AML transplanted in first remission. Disclosures:No relevant conflicts of interest to declare.

Unrelated Cord Blood Transplantation Using Myeloablative Conditioning Regimen for Adults with Acute Myeloid Leukemia in First Complete Remission. A Survey by EUROCORD and the Acute Leukemia Working Party of the EBMT

Abstract 836Patients with high-risk acute myeloid leukemia (AML) have few chances of cure without allogeneic hematopoietic stem cell transplantation (HSCT). HSCT can be used in first remission to cure patients with poor-risk cytogenetics, or as rescue for patients refractory to chemotherapy. Umbilical cord blood (UCB) is one acceptable stem cell source for adult lacking a suitable HLA matched donor.We retrospectively analyzed 134 adults (>18 years) with de novo AML in first complete remission (CR1), who received UCBT as first transplant after a myeloablative conditioning regimen (MAC). Patients were transplanted from 2000–2010 in EBMT centers. Median age at UCBT was 33 years (range 18–63) and median weight was 65 Kg (range 46–112). Based on available cytogenetic and molecular markers at diagnosis (n=111) 45% of patients were classified in the intermediate risk and 31% in unfavorable risk group. Twenty six patients had a FLT3/ITD-positive mutation status. The median time from diagnosis to UCBT was 5.9 months, and the median duration of remission prior to transplant was 104 days.Grafts were composed of 1 (sUCBT) (n=100) or 2 (dUCBT) (n=34) CB units. Thirty two percent of CB units were identical to recipient or had 1 HLA disparity (antigen level for HLA-A and B allelic level for DRB1), while 68% had 2–3 HLA disparities. Median TNC cell dose at infusion was 2.7×10^7/kg in sUCBT and 3.9×10^7/kg in dUCBT.All patients were transplanted using a MAC, from which 60% were busulfan based (n=80). The most frequent regimens used were busulfan+fludarabine+thiotepa (n=56) and cyclophosfamide+TBI12Gy+fludarabine (n=40). ATG was used as part of the conditioning regimen in 73% of patients. GVHD prophylaxis consisted either of CSA ± MMF or CSA ± steroids in 45% and 32% of patients, respectively. Overall, the median follow-up was 22 months (range 3–120), (median follow up 28 months for sUCBT and 22 months for dUCBT).The cumulative incidence (CI) of 60 days neutrophil recovery was 90 ± 3%, (median time of 23 days) and it was 87% for sUCBT and it was 90% dUCBT.At day 100, chimerism test showed full donor chimerism in 92% of patients (data available for 70% of patients who engrafted). At day 100, CI of acute GVHD (grade II–IV) was 19 ± 3%. and it was 12% and 38% for patients transplanted with sUCBT and dUCBT, respectively (p=0.001). Among 34 patients who received a dUCBT, 14 experienced grade II–IV acute GVHD (grade II (n=10), grade III (n=3), grade IV (n=1)) and of those transplanted with a sUCBT, 10 out of 17 had grade II, 4 had grade III, and 3 grade IV.CI of chronic GvHD at 1 year was 20 ± 3%. CI of TRM at 1 year was 32 ± 3%. In the multivariable analysis, TNC dose at infusion >2.9×10^7/kg (p=0.02) was associated with decreased TRM, however in spite of higher incidence of aGVHD dUCBT was not associated with higher TRM. Fifty eight patients died. The causes of death were infection, other transplant-related events (n=45) or relapse (n=13).CI of 2y relapse was 16 ± 4%. It was 15% for those patients transplanted with sUCBT (n=100) and 18% with dUCBT (n=34). Out of 26 patients FLT3/ITD positive, 7 relapsed at a median time of 96 days after UCBT.The 2y probability of leukemia-free-survival (LFS) was 52 ± 2%. There was a trend towards a higher LFS in patients with a longer duration of remission (>66 days, 27% versus 61%, p=0.07). In multivariable model, the use of busulfan in conditioning regimen (HR 2.2, p=0.006) and the use of double UCBT (HR 1.9, p 0.06) were independently associated with better LFS. In fact, LFS was 58% for those patients receiving Busulfan based compared to 42% receiving a TBI based, and it was 58% for dUCBT and 50% for sUCBT.In conclusion, UCBT using one or two CB units is a valid treatment option for adults with high risk AML in CR1 without an HLA identical donor. The best conditioning regimen for single or double UCBT has to be assessed in prospective clinical trials. Disclosures:No relevant conflicts of interest to declare.

The Presence of An Internal Tandem Duplicate of FlT3 Receptor (ITD) Is An Unfavorable Prognostic Factor on the Outcome of Adult Patients with Acute Myeloid Leukemia (AML) Autografted in First Remission (CR1) Only in the Absence of An NPM1 Mutation,

Abstract 4139The prognosis of patients with AML harboring the FlT3 ITD is known to be poor in those patients treated with chemotherapy alone. However, it remains uncertain whether this abnormality has also an impact on outcome following high dose intensification and autologous stem cell transplantation (ASCT).We addressed this question using the EBMT data base: we initially reported on a total of 134 patients in 2010 (Blood 2010, 3356a). Following further queries, we have now extended our study to a total of 357 patients with AML autografted in CR1 between January 2000 to December 2009, and in whom the information on the presence or the absence of FlT3ITD was available. 258 (136 with a normal karyotype) patients were ITD negative and 99 (63 with a normal karyotype) were ITD positive. 96% of the patients received peripheral blood as a source of stem cells. The median follow up was 30 m. (range, 1–118).Patients who were ITD positive had higher white cell counts at diagnosis (54 vs. 12.5 109/L; p<0.0001) and had a higher proportion of slow remitters (needing more than one induction course to achieve CR) (22% vs. 11%; p=0.04). Interestingly, patients who were ITD positive were more frequently found to be NPM1 mutated (59% vs. 40%; p=0.03).In the univariate analysis, Leukemia-Free Survival (LFS) at 3 years was significantly lower in patients who were ITD positive (34±5% vs. 52±4%; p=0.001) and the relapse incidence was higher (58±5% vs. 42±4%; p=0.002). The Non-Relapse Mortality (NRM) rate was similar (8±3% vs. 6±1%; p= 0.7).By multivariate analysis, the only unfavorable prognostic factors for outcome were failure to achieve CR with more than one induction course (slow remitters), and the presence of an ITD, which were associated with higher relapse incidence (p= 0.006; p=0.03) and lower LFS (p=0.05; p=0.005).In this series, it was interesting to observe that the only group with a significantly lower LFS in univariate analysis, was the group of patients who were FlT3ITD positive without NPM1 mutation (23±11% vs. 56±6% for FLT3ITD negative/NPM non-mutated, 46±8% for FLT3ITD negative/NPM mutated and 48±13% for FLT3ITD positive /NPM mutated; p=0.03).We conclude that in the context of autografting for AML in CR1, the presence of a FLT3ITD is an unfavorable prognostic factor only in less than 50% of the patients corresponding to those with the absence of a NPM1 mutation. This study helps to better define the population of patients with AML that would benefit most from intensification with autologous stem cell transplantation. Disclosures:No relevant conflicts of interest to declare.

Cytogenetic Risk Remains a Major Predictor of Outcome in Pediatric AML and ALL Treated with Allogeneic Stem Cell Transplantation,

Abstract 3524 Background:Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) each represent a heterogeneous group of disorders resulting from diverse mechanisms of leukemogenesis. Cytogenetic abnormalities are considered reliable risk-stratification tools in both AML and ALL. Most studies assessing clinical outcome according to cytogenetic risk consider patients treated with conventional intensive chemotherapy. The impact of cytogenetics on outcome in patients treated uniformly with hematopoietic stem cell transplantation (HSCT), especially in the pediatric group, is not well studied. We evaluated whether allogeneic HSCT has an impact on outcome as predicted by cytogenetic risk at diagnosis. Methods:Bone marrow karyotyping and FISH data from 61 pediatric AML patients and 37 pediatric patients with ALL was reviewed and patients divided into two groups according to their cytogenetic risk: one group combined patients with favorable or intermediate risk and the second group comprised patients with adverse-risk cytogenetics. Cytogenetic risk classification was according to WHO and MRC cytogenetic criteria. The AML cohort included 47 (77%) patients treated in their first remission (CR1) while most non-CR1 AML patients were treated with HSCT in CR2. Of the ALL patients, 18 (49%) were treated with HSCT in CR1. The outcome of patients with either favorable/intermediate cytogenetic risk or adverse cytogenetics was compared for AML and ALL patients, first including all patients, then including only CR1 patients. The median age of patients was 8 years (range: 9 months to 13 years). Results:Patients with ALL and favorable / intermediate cytogenetics had significantly longer overall survival (OS) and event-free survival (EFS) as compared with the adverse-risk group (P=0.02 and P=0.03 for OS and EFS, respectively). A similar trend was observed when only CR1 ALL patients were evaluated, although their number is small. Notably, separation between the CR1 ALL and CR2 ALL groups was stronger when only Philadelphia chromosome positive and MLL positive patients were considered (P=0.01 for OS and EFS for all patients; P=0.003 for OS and EFS for CR1patients only). Also for pediatric AML, combined favorable / intermediate-risk cytogenetics was associated with significantly longer OS (P=0.03) and EFS (P=0.04) when all patients were included (Fig. 1). A similar trend was obtained when only CR1 AML patients were considered (P=0.03 for both OS and EFS). Conclusions:This study suggests that stratification of AML and ALL in pediatric patients according to their cytogenetic risk remains relevant even when treated with HSCT and irrespective if patients were treated in CR1 or CR2 after relapse. In particular, MLL gene rearrangements and the Philadelphia chromosome remain poor prognostic factors in pediatric ALL despite HSCT treatment. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Allogeneic stem cell transplantation in first complete remission

The optimal postremission therapy of acute myeloid leukemia (AML) in first complete remission (CR1) is uncertain. This review summarizes the recent developments in the clinical research and therapeutic applications defining the role of allogeneic hematopoietic stem cell transplantation (allo-HCT) in CR1. Molecular markers in combinations with cytogenetics have improved the risk stratification and informed decision-making in patients with AML in CR1. In parallel, several important advances in the transplant field, such as better supportive care, improved transplant technology, increased availability of alternative donors, and reduced-intensity conditioning, have improved the safety as well as access of allo-HCT for a larger number of patients. The progress in risk stratification and in transplant technology dictate that early donor identification search should be initiated for all eligible AML patients in CR1.

A Phase I-II Dose Escalation Trial of Clofarabine Plus Melphalan and Thiotepa Followed by Unmodified Allogeneic Stem Cell Transplant (SCT) for the Treatment of High Risk or Advanced Acute Leukemia

AbstractAbstract 2354High-risk or advanced acute leukemias are associated with poor outcome even with the use of stem cell transplantation (SCT) with or without total body irradiation (TBI). Based on encouraging results with the use of clofarabine (CLO) for reinduction treatment of acute leukemias, we have developed a phase I/II protocol using this agent with melphalan (Mel) and thiotepa (Thio) followed by unmodified SCT for the treatment of patients (pts) with high-risk (HR) leukemias. To date, 28 consecutive pts were treated on, or as per protocol, with 26 pts evaluable for follow-up. There were 15 males and 11 females aged 1–58 years (median 5.3 years). Cytoreduction consisted of CLO at dose level I of 20 mg/m2/day × 5 days (n=23) or at dose level II of 30 mg/m2/day × 5 (n=3), Thio 10 mg/Kg/day × 1 day and Mel 70 mg/m2/day × 2 days. Graft-versus-host disease (GvHD) prophylaxis consisted of tacrolimus and mycophenolate mofetil (MMF), or tacrolimus and methotrexate. Twenty pts had acute lymphoblastic leukemia (ALL) in complete remission (CR1; n=5), CR2 (n=5), CR3 (n=9), or relapse (n=1). Five pts had acute myeloid leukemia (AML), in CR1 (n=1), CR2 (n=2), or CR3 (n=2). One pt had myelodysplastic syndrome (MDS) in RAEB. For the pts with ALL in CR1, very HR features included: Infant MLL (N=2), Philadelphia (Ph1) chromosome (N=2) and Induction failure (N=1). For the pts with ALL in CR2, HR features included: Infant MLL (N=1), 2nd SCT (N=1), Ph1 and 2nd SCT (N=2), while 1 pt had prior CNS infarcts precluding the use of TBI. The one pt with AML in CR1 had M7-AML. This was a first SCT for 14 pts, a 2nd SCT for 11 pts and 3rd SCT for 1 pt, with time from previous SCT to the present one being 5–73 months (median 11.3 mo) for those 12 pts. Donors were HLA-matched siblings (n=8), HLA matched unrelated donors (n=8), or HLA mismatched unrelated donors (N=10). Stem cell grafts were bone marrow (n=12), peripheral blood (n=7) or double cord blood (n=7) stem cells.Twenty four of the 26 evaluable pts engrafted, while 2 pts died prior to engraftment. Toxicity of the SCT cytoreduction included elevation of hepatic transaminases in 17 of 26 evaluable pts (AST elevation of 5–19 fold and ALT elevation of 7–16 fold), with a subsequent normalization in all pts. Mucositis was mostly at acceptable grade 1–2 levels. Two pts developed a syndrome of renal and hepatic insufficiency leading to hepatic veno-occlusive disease (VOD) (1 pt at each of the 2 dose levels). Non-relapse mortality included: VOD (N=2), infections (N=3), treatment related sarcoma, a malignancy secondary to the irradiation received with a prior transplant (N=1).With a follow-up of 3–57 mos (median 21 mos), 15 of the 26 pts are alive, disease-free. Five pts relapsed and 4 died subsequently of disease, while 6 pts died of non-relapse morality. Overall (OS) and disease-free survival (DFS) at 2 years were both 58%. DFS was 56% for pts > 18 years and 53% for pts < 18 years (p =0.36); it was 64% for recipients of a first HSCT and 41% (p=0.97) for recipients of a second or third HSCT. Five pts (4 recipients of unrelated donor SCT; 3 from mismatched donors) developed Grade 2–4 acute GvHD. Four of these pts went on to develop chronic GvHD. Immune reconstitution was rapid; for the evaluable pts, it included absolute CD4 counts > 200 cells/L at 1–3 mos for 15 pts and at 4–8 mos for 4 pts.This cytoreductive regimen represents a promising approach for the transplantation of patients with high risk acute leukemias. It was well tolerated for pts requiring a second SCT and is also associated with rapid immune recovery. Ultimately, a large scale study would need to be done to determine if this approach could offer equal or superior results to TBI containing regimens for ALL or AML. Disclosures:No relevant conflicts of interest to declare.

Autologous Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia in First Complete Remission: A Meta-Analysis of Randomized Trials

Background: For those patients who are not candidates for allogeneic stem cell transplantation (SCT) or who do not have an HLA-matched donor, it is unclear whether consolidation therapy with autologous SCT results in a survival benefit compared with further intensive post-remission non-myeloablative chemotherapy or no further therapy. Methods: A meta-analysis evaluating autologous SCT versus further chemotherapy or no treatment for acute myeloid leukemia (AML) in first complete remission (CR1) was completed. The search used the following combined search terms in Medline, Embase, the Cochrane Controlled Trials Register, the Cochrane Library, the Web of Science and the China National Knowledge Infrastructure. Results: Overall, 13 studies of 12 randomized controlled trials were identified. Four studies were in pediatric patients and 9 were in adults. For adults, AML in CR1 compared with non-SCT, lower relapse and higher transplantation-related mortality were associated with autologous SCT, a significant disease-free survival benefit of autologous SCT was documented, and there was no difference in overall survival when studies were pooled. For pediatric AML in CR1, there were no differences in relapse, transplantation-related mortality, disease-free survival and overall survival. Significantly less survival from relapse impairment was found for autologous SCT. Conclusion: Our results support the conclusion that autologous SCT should not be considered as the first-line post-remission therapy for AML patients in CR1.

Treatment of acute myeloid leukemia (AML) in first remission (CR1) with unrelated donor (UD) allogeneic hematopoietic cell transplantation (HCT).

6532 Background: The benefit of allogeneic HCT in patients with AML in CR1 is frequently offset by excessive transplant related mortality (TRM), which can deny the benefit of the graft-versus-leukemia effect. Conversely, decreasing TRM while preserving antileukemic activity can have marked impact on outcomes. Methods: We transplanted 44 patients in CR1 using the conditioning regimen of IV busulfan (Bu)130 mg/m2 (day-6 to -3), fludarabine (Flu) 40 mg/m2 (day-6 to -3) and antithymocyte globulin (4.0 mg/kg). Graft-versus-host-disease (GVHD) prophylaxis consisted of mini-MTX and tacrolimus, with (n=14) or without pentostatin (n=30). High-resolution allele level HLA typing was performed for all donors/recipients (HLA-A, B, C, DRB1, DQB1 and DPB1). Eligibility: age<65, high/intermediate risk AML. Results: Median age was 48 (range: 13-63) years; 7 patients (16%) had secondary AML. Cytogenetic risk class: intermediate, 41% (N=18), good, 1 case (with CNS disease), and poor, 57% (N=25). Stem cell source was bone marrow in 68% (N=30) and peripheral blood in 32% (N=14). Median follow-up is 28 months. All patients engrafted. Grade II-IV acute (a) GVHD rate was 14% (N=2) in patients who received and 27% (N=8) for those who did not receive pentostatin. Chronic (c) GVHD rate was 39% (N=17; extensive in 7). 100-day and 3-year TRM rate was 5% (N=2) and 16% (N=7), respectively. Six patients (14%) have relapsed and 10 patients (23%) have died (3 of relapse and 7 of TRM causes). 3-year event-free and over all survival is 70% and 78%, respectively. For key outcomes see Table. Conclusions: UD HCT after the myeloablative, reduced toxicity IV Bu-Flu regimen for patients with AML in CR1 yields excellent disease control with low risk for TRM. Patient, disease, and donor characteristics (N)—median follow-up is 28 months 3-year actuarial event-free survival (%) (p value) 3-year actuarial overall survival (%) (p value) All patients (n=44) 70 78 Secondary AML Yes (n=7) 57 (0.4) 56 (0.2) No (n=37) 73 84 Cytogenetic risk category Intermediate (n=18) 82 (0.5) 83 (0.9) Poor (n=25) 62 78 HLA 10/10 Yes (n=39) 70 (0.6) 78 (0.9) No (n=)5 80 80 HLA-DPB1 mismatch 0 (n=11) 58 (0.4) 63 (0.5) 1 (n=22) 78 80 2 (n=11) 78 90 No significant financial relationships to disclose.